Radiation quality-dependence of bystander effect in unirradiated fibroblasts is associated with TGF-β1-Smad2 pathway and miR-21 in irradiated keratinocytes.

Xiaoming Yin,Longxiao Wang,Jianping Cao,Shuyu Zhang,Jingdong Wang,Hongying Yang,Wenqian Tian

doi:10.1038/srep11373

Abstract

Traditional radiation biology states that radiation causes damage only in cells traversed by ionizing radiation. But radiation-induced bystander effect (RIBE), which refers to the biological responses in unirradiated cells when the neighboring cells are exposed to radiation, challenged this old dogma and has become a new paradigm of this field. By nature, RIBEs are the consequences of intercellular communication between irradiated and unirradiated cells. However, there are still some important questions remain unanswered such as whether RIBE is dependent on radiation quality, what are the determining factors if so, etc. Using a transwell co-culture system, we found that HaCaT keratinocytes irradiated with α-particles but not X-rays could induce bystander micronucleus formation in unirradiated WS1 fibroblasts after co-culture. More importantly, the activation of TGF-β1-Smad2 pathway and the consistent decrease of miR-21 level in α-irradiated HaCaT cells were essential to the micronucleus induction in bystander WS1 cells. On the other hand, X-irradiation did not induce bystander effect in unirradiated WS1 cells, accompanied by lack of Smad2 activation and consistent decrease of miR-21 in X-irradiated HaCaT cells. Taken together, these results suggest that the radiation quality-dependence of bystander effect may be associated with the TGF-β1-Smad2 pathway and miR-21 in irradiated cells.

Highlights

Traditional radiation biology states that radiation causes damage only in cells traversed by ionizing radiation
These results suggest that radiation-induced bystander response between HaCaT and WS1 cells may be dependent on radiation quality
Since the demonstration and confirmation of radiation-induced bystander effect (RIBE), the factors involved in the induction of RIBEs have been intensively explored, especially when there is still some debate regarding the universality of this phenomenon

Summary

Introduction

Traditional radiation biology states that radiation causes damage only in cells traversed by ionizing radiation. Both Smad[2] and Smad[7] have been found to play an important role in radiation-induced double strand break (DSB) signaling[31] It remains undefined whether the activation of TGF-β 1/Smad signaling pathways in irradiated cells leading to RIBEs depends on radiation quality. The study from Dickey et al suggests that instead of a primary signaling factor, the changes in the expression of miRNAs are more likely a manifestation of RIBE32, we and others have demonstrated an important mediating role of miRNAs such as miR-21 and miR-66313,33,34 These results support the hypothesis that bystander effect is epigenetically mediated[35,36,37]. It would be interesting to investigate the relationship between miR-21 and TGF-β 1 pathways in irradiated cells sending bystander signals

Methods

Results

Conclusion